title: Radiation- and anthracycline-induced cardiac toxicity and the influence of ErbB2 blocking agents.
abstract: In Her2-positive breast cancer patients, inhibition of epidermal growth factor receptor 2 (ErbB2)-signaling is often combined with chemotherapy and radiotherapy. The risk of cardiac toxicity after anthracyclines and radiotherapy is recognized, but little is known about increased risk when these treatments are combined with ErbB2 inhibition. This study investigated whether ErbB2 inhibition increased radiation or anthracycline-induced toxicity. In an in vitro study, human cardiomyocytes were treated with irradiation or doxorubicin, alone or in combination with trastuzumab, and evaluated for cell survival and growth. Groups of mice received 0 or 14 Gy to the heart, alone or in combination with lapatinib, or 3 × 4 mg/kg doxorubicin alone or in combination with lapatinib. Mice were evaluated 40 weeks after treatment for cardiac damage. Changes in cardiac function ((99m)Tc-Myoview gated SPECT) were related to histomorphology and microvascular damage. Radiation or doxorubicin-induced cardiomyocyte toxicity (in vitro) were not exacerbated by trastuzumab. Cardiac irradiation of mice decreased microvascular density (MVD) and increased endothelial damage in surviving capillaries (decrease alkaline phosphatase expression and increased von Willebrand factor), but these changes were not exacerbated by lapatinib. Inflammatory responses in the irradiated epicardium (CD45+ and F4/80+ cells) were significantly reduced in combination with lapatinib. Irradiation, doxorubicin, and lapatinib each induced cardiac fibrosis but this was not further enhanced when treatments were combined. At the ultra-structural level, both lapatinib and doxorubicin induced mitochondrial damage, which was enhanced in combined treatments. Lapatinib alone also induced mild changes in cardiac function but this was not enhanced in the combined treatments. Trastuzumab did not enhance direct radiation or anthracycline toxicity of cardiomyocytes in vitro. Lapatinib did not enhance the risk of radiation or anthracycline-induced cardiac toxicity in mice up to 40 weeks after treatment, but mitochondrial damage was more severe after doxorubicin combined with lapatinib.
authors.affiliation: Division of Biological Stress Response (H3), The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: Ingar
authors.initials: I
authors.lastname: Seemann
authors.forename: Johannes A M
authors.initials: JA
authors.lastname: te Poele
authors.forename: Ji-Ying
authors.initials: JY
authors.lastname: Song
authors.forename: Saske
authors.initials: S
authors.lastname: Hoving
authors.forename: Nicola S
authors.initials: NS
authors.lastname: Russell
authors.forename: Fiona A
authors.initials: FA
authors.lastname: Stewart
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000473:pathology / Q000528:radiation effects; D004317:Doxorubicin / Q000633:toxicity*; D005355:Fibrosis; D006331:Heart Diseases / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control; D006801:Humans; D000077341:Lapatinib; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000473:pathology / Q000528:radiation effects; D008929:Mitochondria, Heart / Q000187:drug effects / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D010496:Pericardium / Q000528:radiation effects; D011799:Quinazolines / Q000494:pharmacology; D011833:Radiation Injuries, Experimental / Q000473:pathology* / Q000517:prevention & control; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000068878:Trastuzumab; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D061067:Antibodies, Monoclonal, Humanized; D004317:Doxorubicin; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human